Moving the Needle in Undifferentiated Pleomorphic Sarcoma: Trial Design and Key Data

In this episode of OncChats: Moving the Needle in Undifferentiated Pleomorphic Sarcoma, the following experts discuss the rationale behind the Stand Up to Cancer SARC 032 trial (NCT03092323), which examines combining pembrolizumab (Keytruda) with surgery and radiation to prevent metastatic disease in patients with high-risk stage III undifferentiated pleomorphic sarcoma (UPS) and improve survival outcomes without significantly increasing adverse effects (AEs):

• J. Dominic Femino, MD, an orthopaedic surgeon with Keck Medicine of USC and chief of the USC Musculoskeletal Oncology Center
• Lee Zuckerman, MD, an orthopaedic surgeon with Keck Medicine of USC
• Mark Agulnik, MD, a medical oncologist with the USC Norris Comprehensive Cancer Center, part of Keck Medicine of USC
• Andrew Lim, MD, a radiation oncologist with Keck Medicine of USC

Femino: What is the rationale behind the combined treatment [examined in the] Stand Up to Cancer SARC 032 [trial]?

Agulnik: I think there are some absolutes that we are all confident [about] and we all know. Some of them are that for stage III soft tissue sarcomas, it is standard to treat these patients, especially in the extremities and the limb girdles, with surgery and radiation. We know that when we counsel our patients—[those] who are at very high risk for metastatic disease in the future—we have to quote numbers. I think as the tumors get larger in size, and as the grade of the tumor increases, we know that the risk could be over 50%, and that’s historically what we talked to them about.

I think Dr Hu and I would easily say that the majority of our career is spent treating patients with metastatic disease and doing clinical trials for these patients. What we’re trying to do for most of those [cases] is offset the survival curves and try to improve upon the survival of those with metastatic disease. What’s groundbreaking about a trial like this is that we’re not trying to offset a situation that already exists. What we’re trying to do is prevent a situation. So, here is a time when we’re looking at patients who are at high risk for metastatic disease, and what we’re trying to do is see whether we could decrease the risk of the metastatic disease forming and improve outcomes that way as opposed to treating disease that already develops.

When we’re looking at these situations, what we need to figure out is, what are new therapies that will help prevent disease formation vs what are new therapies that will help treat metastatic disease? When we go back and look at some of the work that we’ve done previously, specifically looking at SARC 028 [NCT02301039,] which was a study using immunotherapy [in the form of] pembrolizumab [Keytruda] in patients with a wide variety of soft tissue sarcomas who had metastatic disease, we saw that for patients with undifferentiated pleomorphic sarcoma, they had a response rate that was close to about one-quarter of all patients; I think it was about 23%. When we look at the dedifferentiated liposarcoma and pleomorphic sarcoma, we did see a response rate that was about 1 in 10 patients. So, when we look at those 2 cohorts of patients, it becomes very interesting to see whether we could offset the risk of metastatic disease and improve survival and incorporate pembrolizumab in the neoadjuvant therapy as well as the adjuvant therapy of now patients with stage III disease instead of stage IV disease.

Femino: Dr Agulnik, can you go over the AEs of the study?

Agulnik: Yes, definitely. I think what happens is, that anytime you’re going to introduce something new, you really want to see what impact it has on new symptomatology as well as what impact it has on the treatments that you’re already offering. Does the addition of pembrolizumab cause increased AEs related to the therapies [patients are] already getting? That would be related to radiation or surgery. If we look at [effects] like wound infection and wound dehiscence, it looks very similar when you look at the grade 1, 2, and 3 toxicities associated with the control arm that received radiation and surgery alone vs the group that got the experimental treatment, which was the pembrolizumab, surgery, and radiation. That’s the first thing that you have to check off and say when you counsel patients, that it’s very encouraging that the treatments did not increase AEs related to other therapies, and therefore, from that perspective, it is felt to be safe.

Then, we start to [question,] what are the AEs of pembrolizumab in this [specific] group? That should be no different than the AEs of pembrolizumab in the general population. What we did see was an increased amount of grade 3 anemia, increased grade 3 colitis, increased grade 3 hypothyroidism, and increased grade 3 dyspnea; those were all felt to be AEs related to pembrolizumab. They’re not uncommon AEs. There was nothing new that was discovered with this. For drugs that are currently FDA approved, you always want to make sure that you’re not unmasking something that has not previously been reported and there’s nothing in this study that would indicate that. Most of the AEs are grade 1 and grade 2. So those would be [effects] that would be relatively easy to treat, relatively easy to manage, and ones that should not affect patients’ abilities to perform their activities [associated with] daily living. There were very few grade 3 AEs, which is encouraging, and very few, if any, grade 4 toxicities that are likely unrelated to the treatments that were being given.

And so, as a whole, the AE profile is very safe for patients. The counseling that has to happen for patients—and Dr Hu and I do this all the time—is [focused on] the AEs of immunotherapy. Treatment with pembrolizumab is similar to other immunotherapies we give, and we really know how to manage and control the AEs and watch patients carefully over time to make sure that we catch things quickly so that we could offset AEs getting worse.

Check back tomorrow for the next episode in the series.